Neurodegenerationis the progressive loss of structure or function of neurons, including death ofneurons1 .Cellular signaling is important for biological processincluding growth,differentiation,apoptosis.Signal tansduction pathways playmajor role in coordinating complex function of human body.Tyrosinephosphorylation is one of the main mechanism in this pathwaythat is carried out by the enymes protein tyrosine kinases (PTKs), whichcatalyze the transfer of the ? phosphate of ATP to tyrosine residues on proteinsubstrates. Two classes of PTKs are present in cells: the Transmembrane receptor PTKs contain extracellular ligand bindingdomain,transmembrane domain and intracellular catalytic domain.
2 They transduce the extracellular signal to thecytoplasm by phosphorylating tyrosine residues on the receptors themselves(autophosphorylation) leads to activation of signal transduction cascade 3Nonreceptor PTKs receptor tyrosine kinase relay intracellular signals;they reside in the cytoplasm or in the nucleus rather than as transmembraneproteins and are typically activatedbyinteraction with a protein that is not an extracellular ligand.The RTK family includes the receptors forinsulin ,many growth factors, such as epidermal growth factor ,fibroblastgrowth factorplatelet-derived growth factor, vascular endothelial growth factorandnerve growth factor .Nonreceptortyrosine kinases includes Src and Abl. These kinases are triggered by RTKsand G protein-coupled receptors and receptors of the immune system4.Dysregulationof kinases leads to neurodegenrative diseases,cancer,inflammatorty diseases5 ParkinsonDisease Parkinson’sdisease (PD) is a progressive neurodegenerative disorder due to a selectiveloss of dopaminergic neurons in the substantia nigra pars compacta (SNpc),which leads to a decrease in the synthesis of dopamine (DA)6Role Of TyrosineKinase Receptor In Parkinson Diseasec-Abl Abelsonnon-receptor tyrosine kinase, is activated by oxidative stress and thusactivation of c-Abl may play a role in neurodegenerative disorders7 .c-Ablphosphorylation is increased in PD brain.MPTP metabolized by astrocytes in MPP + (1 –methyl1-4 phenyl pyridinium) .
Thishas toxicity for dopamenergic neuron and affects the survival and functon of subtancia nigra .8Activatedc-Abl can phosphorylate parkin and MPP+ inhibit parkin’s E3 ligase function andaccumulate its toxic substrates, such as PARIS (PARkin Interacting Substrate),aminoacyltRNA synthetase complex-interacting multifunctional protein 2 and far upstreamelement-binding protein 1.When parkin become inactivated, PARIS levels increase,which causemitochondrial dysfunction results in the loss of dopamine neurons 9 .AIMP2is contributor of the loss of DA neurons due to parkin inactivation10 STI-571(Imatinib), a c-Abl inhibitor,restores parkin’s E3 ligase activity, reduces the accumulation of parkinsubstrates, and thereby protects against 1-methyl-4-phenylpyridinium(MPP+)-induced neurotoxicity. The neuroprotection was an absence of tyrosinephosphorylation of parkin and upregulation of the parkin substrates, AIMP2and FBP-1, was suppressed, suggesting that c-Abl inhibition was, in part,protective through maintaining parkin in a catalytically active state .
Inhibitionof c-Abl activation could be an effective disease modifying therapy for PD.11 Duringsporadic PD, activated c-Abl tyrosine phosphorylates parkin, resulting in lossof ubiquitin-ligase activity and leading to accumulation of toxic parkinsubstrates and neuronal death. Imatinibprevents parkin tyrosine phosphorylation by binding to c-Abl, restoringparkin’s E3 ligase activity and cytoprotective function, thus protecting fromcell death and PD.
C-Abltyrosine kinase inhibitor Nilotinib(Tasigna®) is a second-generation inhibitor . It is potent with moderate brainpenetration and is more selective 12 . Substantial protection against DAneuronal loss following MPTP intoxication is resulted by administration ofnilotinib13 .Src family kinases are also implicated in the signalingof cytoskeletal changes, specifically those related to phagocytosis14.
Src kinase is often an activator of PI3K activity .Src kinase role in the signal transduction pathwaylinking LPS activation of TLR4 and NADPH oxidase activation 15.NADPH oxidase (Nox) familyenzymes are one of the main sources of cellular reactive oxygen species.
Theactivation of NADPH oxidase through the phosphorylation the p47phox subunit,its activaton leads to production of superoxide in microglia cells.Squamosamide derivativeFLZ have neuroprotective effects inparkinson disease .FLZ protected motor behavior via the elevation of dopaminelevel. It protects apoptosis of dopamenergic neurons in MPTP induce parkinson.16